ABSTRACT The activation of pattern recognition receptors (PRRs) is a major regulatory checkpoint for the generation of adaptive immunity. Rig-I-like Receptors (RLRs) are a family of PRRs that recognize microbial RNA in the cytosol and induce proinflammatory cytokines and type I and type III interferons. RLRs are important mediators of innate immunity to multiple viral infections. However, the role of RLRs in the regulation of adaptive immunity is still poorly understood. The adaptive immune response to West Nile Virus (WNV) infection is severely dysregulated in the absence of MAVS (also called IPS-1), the essential signaling adaptor of RLRs. In this proposal, we will elucidate the cellular and molecular mechanisms of the RLR-dependent regulation of B cell responses to WNV. This study will provide fundamental conceptual insights that are necessary for the design of novel vaccines to WNV in particular and RNA viruses in general.